GLP-1Agonists, SGLT2 Receptor Blockers and Glucokinase Activators: Novel Therapies for Type 2 Diabetes Steven Edelman, MD Professor of Medicine University of California San Diego Veterans Affair Medical Center

Survival As a Function of A1c in People With Type 2 Diabetes: a Retrospective Cohort Study Lancet 2010, Currie et. al. (28,000 patients 50 years and older) Oral Agents

Insulin +/-Oral Agents

Severe Hypoglycemia and Risks of Vascular Events and Rates NEJM 363:15 Oct. 2010

GLP-1 Effects in Humans: Glucoregulatory Role of Incretins GLP-1 secreted upon the ingestion of food Promotes satiety and reduces appetite

Alpha cells: ↓ Postprandial glucagon secretion

Beta cells: Enhances glucosedependent insulin secretion

Liver: ↓ Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying

Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.

Change in Weight (lb)

Change in A1C (%)

Exenatide vs Insulin Studies: A1C and Weight BYETTA vs Insulin Aspart 70/30

10

Nauck et al1 n=253

9

n=248

BYETTA vs Insulin Glargine

BYETTA vs Insulin Glargine

+ MET or SFU

Heine et al2 n=228

Barnett et al3 N=138 Crossover

n=242

BYETTA vs Insulin Glargine +MET+/-TZD +/-SFU Davies et al4

BYETTA vs Insulin Glargine +/- MET

Bunck et al5

n=118

n=116

n=36

n=33

-1.3%

-1.3%

-0.8%

-0.7%

8 ADA

7 GOAL 6 7

-1.0%

-0.9%

-1.1%

-1.1%

-1.4%

-1.4%

6 4 2 0

9 lb +4.0 lb

12 lb +6.4 lb

-2

10 lb +5.1 lb

13 lb +6.6 lb

10 lb +2.2 lb

-4 -6

-5.5 lb BYETTA

-5.1 lb Insulin aspart 70/30

-4.9 lb

-6.0 lb

-7.8 lb

Insulin glargine

References: 1. Nauck MA, et al. Diabetologia. 2007;50:259-267. 2, Heine RJ, et al. Ann Int Med. 2005;143:559-569; 3. Barnett AH, et al. Clin Ther. 2007;29:2333-2348; 4. Davies M. Presented at EASD. 2008. 5. Bunck MC. Diabetologia. 2007;50:(Suppl 1):S111. Abstract 0251.

See information about hypoglycemia, nausea, or pancreatitis and the Important Safety Information included in this presentation, and the accompanying full Prescribing Information.

Long-Acting Release Technology „ Exenatide

Once Weekly:

–biodegradable polymeric microspheres for extended release –detectable plasma concentrations of exenatide for weeks to months after a single dose Initial release

hydration

Sustained release

diffusion

Bartus RT et al. Science. 1998;281:1161-1162

degradation

erosion

Once Weekly (not FDA approved yet) vs. Twice daily Exenatide BL A1c ~ 8.3

exenatide QW, N=120, BL=8.3% exenatide BID → exenatide QW, N=121, BL=8.2%

Change in A1C (%)

0.0

All subjects received exenatide QW

-0.5

BID exenatide led to 1.5% A1c reduction

-1.0 -1.5

* -2.0 -2.5

* * 0

-2.0%

* *

-2.0%

* * *

6 10 14 18 22 26 30 33 36 40 44 48 52

Time (Weeks) 52-wk Evaluable Population (N=241); LS Mean (SE); *p